Aim: To compare the efficacy and safety of single-dose intravenous nalbuphine versus intravenous tramadol for postoperative analgesia. Materials and Methods: In this prospective randomized study, adults with the American Society of Anesthesiologists physical status class I and II undergoing elective surgeries performed under general anesthesia, resulting in mild-to-moderate pain (n = 60), received either intravenous nalbuphine (10 mg) or tramadol (100 mg). Visual analog scale scores for pain, sedation, and nausea and vomiting were monitored for 4 h and compared between the two groups. Statistical Analysis: The mean scores within the groups were analyzed by paired t-test, whereas between the groups by unpaired t-test. The median scores were analyzed by using Mann–Whitney U test. P value <0.05 was considered statistically significant. Results: Reduction in pain after drug administration was statistically significant at all-time points as compared to before administration in both groups (P < 0.5). Pain reduction after 5 min (P = 0.01) and 30 min (P = 0.03) was significantly better with tramadol, whereas after 4 h, it was better with nalbuphine (P < 0.05). Incidence of nausea and vomiting in tramadol and nalbuphine groups was 23.3% and 40%, respectively. No statistically significant difference was observed in sedation, nausea, and vomiting scores between two groups at any time point (P > 0.05). Conclusion: Intravenous nalbuphine and tramadol both provided effective pain relief in patients with postoperative pain. Tramadol resulted in early pain relief but higher incidence of nausea and vomiting.

To provide effective pain relief for the patients undergoing surgery is one of the major goals of postoperative management. It is desirous to have medicines that provide effective pain relief with minimal side effects. Several medicines that can be administered by different routes are available for the management of pain during postoperative period.[1]

Opioid analgesics are often used for the management of moderate-to-severe type of pain,[2] and opioid-based therapy represents the traditional choice for the management of postoperative pain.[1] These agents have been used in adults[3],[4],[5],[6],[7],[8] as well as in children[9],[10] undergoing surgery. Opioid analgesics are associated with adverse events including sedation, respiratory depression, constipation, nausea, vomiting, and urinary retention.[2] Sedative effect with these agents could be beneficial in patients undergoing surgery,[3] but other effects are undesirable during postoperative period.

Tramadol, a centrally acting analgesic, is commonly used for the control of postoperative analgesia. It has approximately 10% potency as compared with morphine when given parenterally.[11] Tramadol has dual mechanism of action. It acts on opioid receptors as well as inhibits neuronal uptake of norepinephrine and serotonin. Due to non-opioid action, tramadol has lesser risk of producing respiratory depression than other opioids.[12] However, higher incidence of nausea and vomiting is one of the concerns for the use of tramadol in postoperative patients.[13] Nalbuphine is another effective opioid analgesic used for the control of pain after operative procedures.[3] Nalbuphine has been suggested to be a better analgesic having lesser incidence of nausea and vomiting as compared to tramadol during postoperative period.[14] The objective of this study was to evaluate and compare efficacy and safety of single-dose intravenous nalbuphine versus tramadol when used as a postoperative analgesic.

Subject and Methods

In this prospective randomized study, adult patients (18–60 years of age) with the American Society of Anesthesiologists physical status class I and II undergoing elective surgeries performed under general anesthesia, resulting in mild-to-moderate pain were included in the study. The enrolled patients were randomly assigned to either intravenous nalbuphine group or intravenous tramadol group. Randomization was carried out as per the randomization chart. The nature and approximate duration of surgeries (up to 1 h) in both groups were similar.

Patients with physical dependence to opioids; hepatic and renal disease; who were pregnant and lactating, elderly, with diabetes, hypertension, asthma, epilepsy, bleeding disorder, and any symptom of cardiovascular disease; receiving central nervous system depressants, monoamine oxidase, tricyclic antidepressants, selective serotonin reuptake inhibitors, and warfarin; established respiratory depression; a history of hypersensitivity to study drugs; or not willing to participate in the study were excluded. After general and systemic examination, routine laboratory investigations required for the fitness of general anesthesia were performed.

Preanesthetic medications included intravenous glycopyrrolate (4 μg/kg), midazolam (0.03 mg/kg), ondansetron (0.1 mg/kg), and fentanyl (2 μg/kg). Induction of anesthesia was performed with either thiopentone (5 mg/kg) or propofol (2 mg/kg) intravenously, whereas anesthesia was maintained with isoflurane (1%–2%) with nitrous oxide and oxygen on circle absorber system with intermittent positive pressure ventilation. Atracurium–0.75 mg/kg of loading dose and 0.2 mg/kg of maintenance dose–or vecuronium (0.1 mg/kg) was used for muscle relaxation. Patients were subjected to endotracheal intubation or laryngeal mask airway. No other analgesic was used intraoperatively. After the procedure, relaxation was reversed with intravenous glycopyrrolate (8 μg/kg) and neostigmine (0.05 mg/kg).

After extubation, patients randomly received either nalbuphine (10 mg) or tramadol (100 mg), both intravenously administered in a drip of 100-mL normal saline over 15–20 min. Intravenous paracetamol was administered as rescue medication, if required, depending on visual analog scale (VAS) pain score. Pulse rate, systolic and diastolic blood pressure levels, and respiratory rate (RR) were assessed before administration of the drug, after 5 min, 30 min, 1 h, 2 h, and hourly until 4 h. The end points of the study were changes in pain severity, sedation, and nausea and vomiting till 4 h after surgery.

Pain severity was assessed by the VAS score of 10. The score was assessed as: 0, no pain and 10, worst imaginable pain. Sedation was assessed with 4-point Pasero Opioid-induced Sedation Scale[15]: 1, awake and alert; 2, slightly drowsy, easily aroused; 3, frequently drowsy, arousable, drifts off to sleep during conversation; and 4, somnolent, minimal or no response to verbal or physical stimulation. Nausea and vomiting was assessed on a 5-point scale: 0, no nausea or vomiting; 1, mild nausea, no treatment required; 2, nausea only, antiemetic prescribed until resolution; 3, vomiting, antiemetic prescribed until resolution; and 4, nausea/vomiting that did not respond to antiemetic. Ondansetron was used as an antiemetic for the control of vomiting.

Assessment of all scores was performed before administration of the drug, after 5 min of drug administration, 1 h, 2 h, and then hourly until 4 h.

The study was started after obtaining institutional ethics committee approval and written informed consent from the patients.

Statistical Analysis

Continuous variables are presented as mean and standard deviation (SD), whereas categorical variables are presented as number and percentages. Mean scores within the groups were analyzed by paired t-test, whereas between the groups by unpaired t-test. Chi-square test was used to examine the difference between two groups for rescue medicine. Mann–Whitney U test was used to analyze difference in the median scores. P value < 0.05 was considered as statistically significant.

Results

Demographic characteristics

A total of 60 patients of either sex were included in the study. Thirty patients each received intravenous nalbuphine and tramadol [Figure 1]. No statistically significant difference was observed in the mean age, height, and weight of the patients in the two groups [Table 1].

Change in the pulse rate was statistically significant after the administration of tramadol until 120 min as compared with nalbuphine. At 3 and 4 h, no significant difference was observed between two groups. No patient in either group showed bradycardia or tachycardia. Except at 2 h, no significant difference was reported in the RR between two groups [Table 2].

No significant difference was observed in the systolic or diastolic blood pressure levels between two groups at any time point [Table 3]. Overall, tramadol and nalbuphine both showed stable hemodynamics.

The mean VAS scores for pain at all-time points in both the groups are shown in [Figure 2]. The mean VAS score for pain in tramadol and nalbuphine reduced from 5.00 and 5.70 preoperatively to 3.9 and 5.2, respectively, after 5 min of administration. The mean VAS score for pain in tramadol group and nalbuphine group at 30 min, 1 h, 2 h, 3 h, and 4 h was 3.2, 3.2, 3.1, 3.3, and 3.7 and 4.1, 3.6, 3.1, 2.7, and 2.5, respectively.

Figure 2: Comparison of mean VAS score between tramadol and nalbuphine groups before and after administration

The percentage reduction in VAS score after 5 min, 30 min, 1, 2, 3, and 4 h of administration of tramadol was 21.4%, 36.6%, 36%, 38%, 34.6%, and 26.6%, respectively. The respective percentage reduction in VAS scores with nalbuphine was 9.3%, 28.6%, 36.5%, 45.6%, 52.6%, and 56.1%, respectively. The reduction in pain till 4 h in both the groups was statistically significant at all-time points as compared to before administration of medicine (P < 0.05 for all-time points).

Comparison between groups showed no significant difference in the VAS score before administration of drug (P = 0.1). The difference after 5 min (P = 0.01) and after 30 min (P = 0.03) was statistically significant and was in favor of tramadol. After 4 h of drug administration, difference in the VAS score was significantly better with nalbuphine as compared with tramadol (P < 0.05). After 1, 2, and 3 h of drug administration, no significant difference was observed between two groups (P > 0.5).

Rescue analgesia was required in 10 (33.3%) and 6 (20%) patients in the tramadol and nalbuphine groups, respectively. The difference between two groups was not statistically significant (P = 0.24).

Incidence of nausea and vomiting in tramadol and nalbuphine groups was 23.3% and 40%, respectively. The median score for nausea and vomiting in both groups was similar at baseline (0 in both groups). No difference was observed between tramadol and nalbuphine groups for the median scores after 5 min (1 vs. 0; P > 0.05) and 30 min (2 vs. 0; P > 0.05). The median scores at 1, 2, 3, and 4 h were zero in both groups.

Discussion

Acute postoperative pain is a concern among most of the patients undergoing surgical procedures. Similarly, inadequate pain relief is also a common problem in these patients, which may adversely affect their quality of life and functions.[16] Opioid analgesics such as tramadol and nalbuphine are commonly used for the management of postoperative pain.

Tramadol acts by dual mechanism, that is, opioid and non-opioid mechanisms.[17] The non-opioid mechanism of tramadol involves inhibition of reuptake of norepinephrine and serotonin.[12] It is one of the popular agents for the treatment of pain because of its availability in different formulations, including those that are used for oral and parenteral routes.[18],[19]

Nalbuphine is a synthetic opioid agonist–antagonist with potent analgesic action, which can be used by subcutaneous, intramuscular, and intravenous routes. It can be a valuable option for the treatment of moderate-to-severe postoperative pain.[20] Intravenous route is preferred for acute pain such as postoperative pain. In this prospective study, we compared efficacy of intravenous tramadol and nalbuphine in providing relief from postoperative pain.

We found both drugs to be significantly effective in providing postoperative analgesia until 4 h after surgery. In a prospective, randomized, double-blind study from India comparing nalbuphine (0.25 mg/kg) versus tramadol (2 mg/kg), VAS score for pain was not significantly different between two groups until 3 h of surgery.[14] We observed better pain relief with tramadol until 30 min postoperatively, whereas at 1, 2, and 3 h, no significant difference was observed between two groups. In our study, after 4 h of drug administration, nalbuphine provided better pain relief, whereas Kumar et al.[14] observed similar results after 3 h after surgery.

Another study from India reported better postoperative pain relief with nalbuphine compared with tramadol in patients undergoing orthopedic operative procedures.[13] In this study, the study medications were administered eight hourly unlike single dose in our study.

A comparative study among patients undergoing gynecological laparotomies reported that those in the tramadol group needed lesser rescue boluses and less amount of medicine during initial 12 h after surgery as compared to nalbuphine group.[21] However, in another study[13] among patients undergoing orthopedic procedures, use of rescue medicine was higher in the tramadol group as compared to nalbuphine group when given eight hourly. In our study, numerically more number of patients in the tramadol group required rescue analgesia with intravenous paracetamol compared to nalbuphine group, but the difference was not statistically significant.

Nausea, vomiting, and sedation are among the most common side effects of tramadol and other opioids.[2],[18] A comparative study[14] has reported significantly higher mean sedation scores at second and fourth postoperative hour in nalbuphine group as compared with tramadol group. Solanki et al.[13] have reported higher sedation score with intravenous nalbuphine as compared to tramadol when given eight hourly. In our study, no significant difference was observed in the sedation score between two drugs. Similar to other studies,[13],[14] we also observed higher rate of nausea and vomiting in tramadol group. However, we did not find difference in the median scores of nausea and vomiting between two groups.

Maintenance of hemodynamic stability in the early postoperative period is important. We monitored pulse rate and blood pressure levels at regular intervals till 4 h after surgery. A comparative study has shown that nalbuphine provides better hemodynamic stability during early postoperative period as compared to morphine in patients with cardiac surgery.[22] Solanki et al.[13] reported better hemodynamic stability with nalbuphine as compared with tramadol during postoperative period in patients undergoing orthopedic surgical procedures. In our study, although at some time points, a statistically significant difference was observed in the pulse rate between two groups, it was not clinically significant. We did not observe tachycardia or bradycardia in any patient in both the groups. Similarly, we did not observe clinically significant difference in the blood pressure levels between two groups. Respiratory depression is also an important concern in patients receiving opioids.[2] In our study, no significant difference was observed in the RR between two groups till 4 h after surgery.

We did not evaluate improvement in pain on movement. This is one of the limitations of our study. Limited sample size was another limitation of our study. Single dose of study medication may not provide significant insights into safety and efficacy of the medications. Moreover, follow-up of patients was carried out for only 4 h for the study purpose. Larger studies are required to confirm our observations.

Conclusion

Single-dose intravenous nalbuphine and tramadol both were effective in providing pain relief in patients undergoing surgical procedures under general anesthesia. Tramadol resulted in early pain relief but higher incidence of nausea and vomiting.

Acknowledgement

We acknowledge the support and assistance of Dr. Anant Patil in writing and editing the manuscript.